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A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer.

Publication ,  Journal Article
Whitley, MJ; Cardona, DM; Lazarides, AL; Spasojevic, I; Ferrer, JM; Cahill, J; Lee, C-L; Snuderl, M; Blazer, DG; Hwang, ES; Greenup, RA ...
Published in: Sci Transl Med
January 6, 2016

Local recurrence is a common cause of treatment failure for patients with solid tumors. Intraoperative detection of microscopic residual cancer in the tumor bed could be used to decrease the risk of a positive surgical margin, reduce rates of reexcision, and tailor adjuvant therapy. We used a protease-activated fluorescent imaging probe, LUM015, to detect cancer in vivo in a mouse model of soft tissue sarcoma (STS) and ex vivo in a first-in-human phase 1 clinical trial. In mice, intravenous injection of LUM015 labeled tumor cells, and residual fluorescence within the tumor bed predicted local recurrence. In 15 patients with STS or breast cancer, intravenous injection of LUM015 before surgery was well tolerated. Imaging of resected human tissues showed that fluorescence from tumor was significantly higher than fluorescence from normal tissues. LUM015 biodistribution, pharmacokinetic profiles, and metabolism were similar in mouse and human subjects. Tissue concentrations of LUM015 and its metabolites, including fluorescently labeled lysine, demonstrated that LUM015 is selectively distributed to tumors where it is activated by proteases. Experiments in mice with a constitutively active PEGylated fluorescent imaging probe support a model where tumor-selective probe distribution is a determinant of increased fluorescence in cancer. These co-clinical studies suggest that the tumor specificity of protease-activated imaging probes, such as LUM015, is dependent on both biodistribution and enzyme activity. Our first-in-human data support future clinical trials of LUM015 and other protease-sensitive probes.

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Published In

Sci Transl Med

DOI

EISSN

1946-6242

Publication Date

January 6, 2016

Volume

8

Issue

320

Start / End Page

320ra4

Location

United States

Related Subject Headings

  • Tissue Distribution
  • Sarcoma
  • Peptide Hydrolases
  • Neoplasms
  • Mice
  • Metabolome
  • Injections, Intravenous
  • Humans
  • Fluorescent Dyes
  • Female
 

Citation

APA
Chicago
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MLA
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Whitley, M. J., Cardona, D. M., Lazarides, A. L., Spasojevic, I., Ferrer, J. M., Cahill, J., … Brigman, B. E. (2016). A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer. Sci Transl Med, 8(320), 320ra4. https://doi.org/10.1126/scitranslmed.aad0293
Whitley, Melodi Javid, Diana M. Cardona, Alexander L. Lazarides, Ivan Spasojevic, Jorge M. Ferrer, Joan Cahill, Chang-Lung Lee, et al. “A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer.Sci Transl Med 8, no. 320 (January 6, 2016): 320ra4. https://doi.org/10.1126/scitranslmed.aad0293.
Whitley MJ, Cardona DM, Lazarides AL, Spasojevic I, Ferrer JM, Cahill J, et al. A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer. Sci Transl Med. 2016 Jan 6;8(320):320ra4.
Whitley, Melodi Javid, et al. “A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer.Sci Transl Med, vol. 8, no. 320, Jan. 2016, p. 320ra4. Pubmed, doi:10.1126/scitranslmed.aad0293.
Whitley MJ, Cardona DM, Lazarides AL, Spasojevic I, Ferrer JM, Cahill J, Lee C-L, Snuderl M, Blazer DG, Hwang ES, Greenup RA, Mosca PJ, Mito JK, Cuneo KC, Larrier NA, O’Reilly EK, Riedel RF, Eward WC, Strasfeld DB, Fukumura D, Jain RK, Lee WD, Griffith LG, Bawendi MG, Kirsch DG, Brigman BE. A mouse-human phase 1 co-clinical trial of a protease-activated fluorescent probe for imaging cancer. Sci Transl Med. 2016 Jan 6;8(320):320ra4.

Published In

Sci Transl Med

DOI

EISSN

1946-6242

Publication Date

January 6, 2016

Volume

8

Issue

320

Start / End Page

320ra4

Location

United States

Related Subject Headings

  • Tissue Distribution
  • Sarcoma
  • Peptide Hydrolases
  • Neoplasms
  • Mice
  • Metabolome
  • Injections, Intravenous
  • Humans
  • Fluorescent Dyes
  • Female